Abstract 984: Optimizing first-line systemic therapy selection in advanced hepatocellular carcinoma (HCC): A biomarker approach using circulating cell-free DNA (cfDNA) (atezolizumab plus bevacizumab vs. lenvatinib vs. sorafenib)

Abstract Background: With the emergence of new immune checkpoint inhibitors and tyrosine kinase inhibitors for advanced HCC, determining the optimal first-line therapy is challenging due to the lack of precise biomarkers. This underscores the urgent need for biomarker-based strategies for treatment decisions. Methods: This prospective biomarker study analyzed plasma cfDNA from 267 advanced HCC patients treated with first-line sorafenib (S) (n=212), lenvatinib (L) (n=32), or atezolizumab plus bevacizumab (AteBev) (n=23). Low-depth whole-genome sequencing was performed on cfDNA to identify genome-wide copy number alterations (CNAs). The 'I-score' was established to quantify genomic instability, calculated as the sum of absolute Z-scores of sequenced reads for each chromosome. The treatment outcomes of the three different therapies were compared based on the I-score. The I-score cutoff to differentiate high from low genomic instability was set the level separating progressive disease (PD) from non-PD at the first response evaluation .Results: Patient demographics and disease characteristics were predominantly male (90.6%) with a median age of 59 years. The majority had an ECOG performance status of 1 (55.4%), HBV etiology (81.3%), and were classified as Child-Pugh class A (88.8%), with most presenting at BCLC stage C (95.1%). The high I-score group (n=164) exhibited a higher prevalence of macrovascular invasion (56.8% vs. 24.6%; p<0.001), lymph node metastasis (39.6% vs. 27.2%; p=0.038), and bone metastasis (14.6% vs. 4.9%; p=0.012) but lower peritoneal metastasis (5.5% vs. 12.6%; p=0.039) compared to the low I-score group (n=103). The high I-score group showed a worse disease control rate (50.6% vs. 74.8%; p<0.001), shorter time to progression (TTP) (median, 2.1 vs. 4.3 months; p<0.001), and poorer overall survival (OS) (6.0 vs. 18.5 months; p<0.001) compared to the low I-score group. Treatment efficacy varied within the high I-score group, with AteBev showing the most favorable outcomes: the median TTP was 6.0 months for AteBev vs. 4.1 months for L vs. 1.8 months for S (p=0.005), and the median OS was not reached for AteBev vs. 7.6 months for L vs. 5.4 months for S (p=0.036). However, in the low I-score group, there were no significant differences in TTP and OS among the treatment types: the median TTP was 9.4 months for AteBev vs. 3.9 months for L vs. 4.2 months for S (p=0.665), and the median OS was not reached for AteBev vs. 9.9 months for L vs. 18.8 months for S (p=0.412). Conclusions: The I-score, reflecting genome-wide CNA in cfDNA, has potential as a prognostic biomarker for outcomes in advanced HCC patients receiving first-line treatments. It may be instrumental in guiding the selection of the most appropriate therapy. Citation Format: Sook Ryun Park, Bo Hyun Kim, Ye-eun Lee, Ju Hyun Shim, Danbi Lee, Jonggi Choi, Eun-Hae Cho. Optimizing first-line systemic therapy selection in advanced hepatocellular carcinoma (HCC): A biomarker approach using circulating cell-free DNA (cfDNA) (atezolizumab plus bevacizumab vs. lenvatinib vs. sorafenib) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 984.